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SHR Neuro Krebs Kardio Lipid Stoffw Microb

Erkan-Candag, H; Clarke, A; Tiapko, O; Gsell, MAF; Stockner, T; Groschner, K.
Diacylglycerols interact with the L2 lipidation site in TRPC3 to induce a sensitized channel state
EMBO REP. 2022; e54276 Doi: 10.15252/embr.202154276 [OPEN ACCESS]
Web of Science PubMed PUBMED Central FullText FullText_MUG

 

Führende Autor*innen der Med Uni Graz
Erkan Candag Hazel
Groschner Klaus
Co-Autor*innen der Med Uni Graz
Gsell Matthias
Tiapko Oleksandra
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Abstract:
Coordination of lipids within transient receptor potential canonical channels (TRPCs) is essential for their Ca2+ signaling function. Single particle cryo-EM studies identified two lipid interaction sites, designated L1 and L2, which are proposed to accommodate diacylglycerols (DAGs). To explore the role of L1 and L2 in TRPC3 function, we combined structure-guided mutagenesis and electrophysiological recording with molecular dynamics (MD) simulations. MD simulations indicate rapid DAG accumulation within both L1 and L2 upon its availability within the plasma membrane. Electrophysiological experiments using a photoswitchable DAG-probe reveal potentiation of TRPC3 currents during repetitive activation by DAG. Importantly, initial DAG exposure generates a subsequently sensitized channel state that is associated with significantly faster activation kinetics. TRPC3 sensitization is specifically promoted by mutations within L2, with G652A exhibiting sensitization at very low levels of active DAG. We demonstrate the ability of TRPC3 to adopt a closed state conformation that features partial lipidation of L2 sites by DAG and enables fast activation of the channel by the phospholipase C-DAG pathway.

Find related publications in this database (Keywords)
diacylglycerol
lipid regulation
lipid-protein interactions
TRPC channels
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